1. Field of the Invention
The present invention is directed to the use of inhibitors of glycogen synthase kinase-3β (GSK-3β) to promote bone formation and treat bone metabolic diseases such as osteoporosis.
2. State of the Art
Glycogen synthase kinase (GSK) is a serine/threonine kinase for which two isoforms, α and β, have been identified. Glycogen synthase kinase-3β (GSK-3β) was originally identified as a protein kinase which phosphorylated and inactivated glycogen synthase, a key enzyme regulating insulin-stimulated glycogen synthesis ((see Embi et al., Eur. J. Biochem. 107, 519-527, (1980); Rylatt et al., Eur. J. Biochem. 107, 529-537, (1980); and Vandenheede et al., J. Biol. Chem. 255, 11768-11774, (1980)). Subsequently, it was discovered that GSK-3β is inhibited upon insulin activation thereby allowing the activation of glycogen synthase. Therefore, inhibition of GSK-3β stimulates insulin-dependent processes and is useful in the treatment of type 2 diabetes which is characterized by decreased sensitivity to insulin and an increase in blood glucose level. A number of drugs such as 5-iodotubercidin®, metformin®, troglitazonem®, have been used to treat diabetes. These drugs however have limited application because metformin® can cause hypoglycemia, troglitazonem® can cause severe hepatoxicity and 5-iodotubercidin®, a known GSK-3 inhibitor, inhibits other serine/threonine and tyrosine kinases.
Recently, it has been discovered that GSK-3β plays a role in pathogenesis of Alzheimer's disease ((see Lovestone et al., Current Biology, 4, 1077-86 (1994), Brownlees et al., Neuroreport, 8, 3251-3255 (1997), Takashima et al., PNAS 95, 9637-9641 (1998), and Pei et al., J Neuropathol. Exp., 56, 70-78 (1997)) and bipolar disorder (see Chen et al., J. Neurochemistry, 72, 1327-1330 (1999)). It has also been discovered that GSK-3β is involved in blocking of early immune response gene activation via NF-AT and regulation of apoptosis (see Beals et al., Science, 275, 1930-33 (1997) and Pap, M. et al. J. Biochem. 273, 19929-19932, (1998)). Additionally, GSK-3β is reported to be required for the NF-κB mediated survival response in the TNF-α signalling pathway involved in the proinflammatory response to infection ((Hoeflich et.al., Nature, 406, 86-90 (2000)).
Furthermore, GSK-3β is also known to regulate the degradation of a protein (β-catenin) which controls the activity of TCF family of transcription factors ((see., Dale, T. C., Biochem. J. 329, 209-223 (1998); Clevers, H. & van de Wetering, M., Trends in Genetics 13, 485-489 (1997); Staal, F. J. T. et al., International Immunology 11, 317-323 (1999)). The pathway has been shown to regulate the transformation of colonic epithelial cells.
GSK-3β inhibitors are described in the following references: WO99/65897 (U.S. Pat. No. 6,417,185 (Chiron)), WO 01/20727A1 (U.S. Pat. No. 6,361,346 (Sanofi-Synthelabo)), EP 1 136 493 A1(Sanofi-Synthelabo), EP 1 136 489 A1(Sanofi-Synthelabo), EP 1 136 486 A1 (Sanofi-Synthelabo), EP 1 136 483 A1(Sanofi-Synthelabo), EP 1 136 099A1(Sanofi-Synthelabo), ) WO 2000/021927 (SKB), WO 2001/049709, WO 2001/056567 (US 2001039275 (Novo Nordisk)), WO 2001/081345, WO 2001/085685, WO 2001/009106 (SKB) and WO2001/52862 (U.S. Pat. No. 6,323,029 (Isis)), WO2001/37819, WO2001/60374, EP 1 106 180A1 (CNRS), WO2000/38675 (SKB), WO 2002096905 (Vertex), WO 2002088078 (Vertex), WO 2002085909, US 2002156087, US 2002147146, WO 2002079197, WO 2002066480, WO 2002065979, WO 2002062795, WO 2002062789, WO 2002059112, WO 2002050079, WO 2002050073, WO 2002050066, WO 2002032896, WO 2002024694, WO 2002022604, WO 2002020495, WO 2002018346, EP 1184385, EP 1184384, EP 1184383 and WO 2001085685.